雄激素联合分化诱导剂治疗低危骨髓增生异常综合征

目的 探讨低危骨髓增生异常综合征（ＭＤＳ）的治疗方法。方法 对４５例低危ＭＤＳ患者,采用康力龙及联合全反式维甲酸（ＡＴＲＡ）或１,２５（ＯＨ）２Ｄ３分三组进行治疗。结果 康力龙组、康力龙＋ＡＴＲＡ组、康力龙＋１,２５（ＯＨ）２Ｄ３组基本缓解率分别为１０％、２８．７％、２８．６％,总有效率分别为４０％、６７．９％、７１％。结论 雄激素联合分化诱导剂治疗低危ＭＤＳ,效果好,副作用少。     

In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies

Low-dose demethylating agents such as 5-aza-2'-deoxycytidine (decitabine, DAC) and 5-azacytidine (azacitidine, Vidaza) have been explored for the treatment of myelodysplasia, acute myeloid leukemia, and hemoglobinopathies since the early 1980s, aiming to revert a methylator phenotype. Originally, the treatment rationale in hemoglobinopathies was to achieve demethylation of the hypermethylated and hence silent gamma-globin gene locus, thus reactivating synthesis of hemoglobin F (HbF). In myelodysplastic syndrome (MDS), cytogenetic analyses are mandatory for risk stratification and for monitoring response to drug treatment. The current knowledge regarding cytogenetic subgroups as predictors of response to low-dose decitabine in MDS as well as cytogenetic responses caused by demethylating agents is summarized in this review. Decitabine treatment is associated with a response rate that is higher in patients with high-risk cytogenetics (i.e., complex karyotype and/or abnormalities of chromosome 7) than in patients with intermediate-risk cytogenetics (two abnormalities or single abnormalities excluding 5q-, 20q-, and -Y). Following decitabine treatment of patients with abnormal karyotype, approximately one-third achieve a major cytogenetic response that can be confirmed by FISH analyses, while in two-thirds of patients, the abnormal karyotype persists but hematologic improvement may be observed during continued treatment. The most frequently studied gene in myelodysplasia is the cell cycle regulator p15(INK4b). Hypermethylation of p15(INK4b) in MDS is reversed during treatment with decitabine, resulting in reactivation of this gene. In hemoglobinopathies, treatment with demethylating agents leads to reactivation of fetal HbF (the gamma-globin gene locus also possibly being another target for reactivation in MDS), and thus, HbF may potentially act as surrogate marker for activity of decitabine. Other, thus far unidentified hypermethylated genes may also be targets for demethylating agents.     

骨髓增生异常综合征患者细胞遗传学检测临床意义

目的研究骨髓增生异常综合征患者细胞遗传学异常表型及其与MDS患者转归关系。方法采用骨髓细胞直接法或24~48小时培养法制备染色体,用RHG技术进行核型分析。结果MDS患者异常染色体出现率46%,主要有 8、-7、5q-、11q-、20q-,并有复杂异常核型。复杂异常核型患者急性白血病转化率明显高于核型正常者。结论MDS患者有异常核型者易转为急性白血病,异常染色体出现与该类患者转归有直接关系,核型分析对MDS患者预后判断有重要价值。     

Clinical and cytogenetic responses to granulocyte-macrophage colony-stimulating factor in therapy-related myelodysplasia.

We treated 10 patients with a therapy-related myelodysplastic syndrome with escalating doses of granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) in a phase II trial and used sequential cytogenetic analyses to determine whether there was stimulation of nonclonal hematopoiesis. The GM-CSF was administered by continuous intravenous infusion over 2 hours daily for 14 days, followed by a 14-day rest period. The initial starting dose was 60 micrograms/m2/d. The GM-CSF dose was escalated within individual patients to 125 micrograms/m2, 250 micrograms/m2, and then 500 micrograms/m2/d until the peripheral blood neutrophil count at least doubled and exceeded 1,000/microL. GM-CSF treatment then continued in monthly maintenance cycles. During 57 treatment courses, the neutrophil count increased in 52 but only doubled and exceeded 1,000/microL in 21. Mild eosinophilia was stimulated in five patients, but only two had greater than 1,000 eosinophils/microL. In only three patients was any stimulation of platelet or red blood cell production observed, and thus, little change in transfusion requirements occurred. The bone marrow karyotypes from individual patients either remained completely abnormal or became increasingly abnormal over the course of treatment. We found no evidence that GM-CSF preferentially stimulated normal marrow stem cells to proliferate or had the ability to eradicate the cytogenetically abnormal clone by inducing terminal differentiation. Although the effect on granulopoiesis was transient and dependent on continued GM-CSF treatment, the increase in the neutrophil count was clinically important in some patients, allowing more effective control of ongoing infections.     

Therapy-related myelodysplasia in a patient with Rothmund-Thomson syndrome

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder of which approximately 300 cases have been reported in the literature. Patients with RTS often present early in life with skeletal and dental abnormalities, short stature, juvenile cataracts, and a characteristic poikilodermal rash. They are at increased risk for the development of osteosarcoma that usually presents by the second decade of life. The genetic defects underlying RTS are truncating mutations in RECQL4, a gene involved with chromosomal stability. Several cases of primary hematological malignancies have been reported in RTS, but it is unclear whether patients with RTS are at higher risk to develop either primary or secondary hematological malignancies. We report a patient with RTS who presented to our clinic at the age of 7, subsequently developed multifocal and recurrent osteosarcoma that was followed by the development of a myelodysplastic syndrome with subsequent progression to acute myeloid leukemia.     

Down综合征并发先天性心脏病的临床分析

目的:总结分析Down综合征(Down’s syndrome)并发的先天性心脏病畸形及血流动力学资料。方法:2008年7月~2012年10月,采用经胸二维超声心动图并彩色多普勒显像及右心导管/心血管造影检查方法,诊断36例并发先心病的Down综合征患者,本文通过36例临床资料分析,探讨Down综合征并发的先心病畸形及其血流动力学。结果:36例患者中室间隔缺损(VSD)10例,房室间隔缺损(AVSD)6例,动脉导管未闭(PDA)6例,房间隔缺损(ASD)2例,ASD+PDA 2例,ASD+VSD 1例,ASD+PDA+VSD 1例,VSD+PDA 4例,PDA+二叶主动脉瓣(BAV)1例,法洛四联症(TOF)2例,TOF+ASD 1例,18例有肺动脉高压者,其中5例为阻力型肺动脉高压。结论:①Down综合征并发的心血管畸形中,以VSD、AVSD和PDA最为常见,并常并发ASD、TOF。②在无肺动脉狭窄的患者中,约50%并发有肺动脉高压。     

Clonal analysis of hematopoietic stem-cell differentiation in vivo.

Previous work has shown that the 0.02-0.05% of adult mouse bone marrow cells that bear the cell surface phenotype Thy-1loLin-Sca-1+ are enriched 1000- to 2000-fold for hematopoietic stem-cell activity in a variety of assays. When 50-100 cells of this phenotype are injected into an irradiated animal, they can permanently repopulate the entire hematopoietic system. In the present study, limiting-dilution and single-cell experiments were used to address the question of how individual Thy-1loLin-Sca-1+ stem cells contribute to repopulation of the hematopoietic system following irradiation. We calculated that 1 of 13 Thy-1loLin-Sca-1+ cells formed a clone comprising greater than 1% of peripheral white blood cells 3-7 weeks after injection. The majority of these clones included both lymphoid and myeloid lineages. Approximately one-third of the clones continued to produce new blood cells for 9 weeks or more, but the remainder disappeared earlier, including many that were multilineage. Thus, while the majority of Thy-1loLin-Sca-1+ bone marrow cells whose progeny are detected in the in vivo repopulation assay are pluripotential, only a subset undergo long-term self-renewal in vivo. Repopulation appears to be oligoclonal when limiting numbers of Thy-1loLin-Sca-1+ cells are injected. However, the number of clones contributing to hematopoiesis increases in proportion to the number of Thy-1loLin-Sca-1+ cells injected, bringing into question the notion that steady-state hematopoiesis in normal individuals is oligoclonal.     

Down综合征并发先天性心脏病的临床分析

目的：总结分析Down综合征（Down’s syndrome）并发的先天性心脏病畸形及血流动力学资料。方法：2008年7月-2012年10月,采用经胸二维超声心动图并彩色多普勒显像及右心导管／心血管造影检查方法,诊断36例并发先心病的Down综合征患者,本文通过36例临床资料分析,探讨Down综合征并发的先心病畸形及其血流动力学。结果：36例患者中室间隔缺损（VSD）10例,房室间隔缺损（AVSD）6例,动脉导管未闭（PDA）6例,房间隔缺损（ASD）2例,ASD＋PDA2例,ASD＋VSD1例,ASD＋PDA＋VSD1例,VSD＋PDA4例,PDA十二叶主动脉瓣（BAV）1例,法洛四联症（TOF）2例,TOF＋ASD1例,18例有肺动脉高压者,其中5例为阻力型肺动脉高压。结论：①Down综合征并发的心血管畸形中,以VSD、AVSD和PDA最为常见,并常并发ASD、TOF。②在无肺动脉狭窄的患者中,约50％并发有肺动脉高压。     

Molecular cytogenetic analysis of monosomy 7 in pediatric patients with myelodysplastic syndrome

Monosomy 7 is a non-random cytogenetic abnormality that is frequently associated with myelodysplastic syndromes (MDS). Twenty-four bone marrow samples from five pediatric patients with MDS were analysed using both traditional and Interphase cytogenetic analysis. The majority of the metaphases were monosomic for chromosome 7 while interphase cytogenetic analysis consistently detected a disomic cell population in nondividing cell populations. This suggests that the monosomy 7 cells have a distinct proliferative advantage compared to the disomic cell population. The results demonstrate that interphase cytogenetic analysis provides important cytogenetic information about non-dividing cell subpopulations, enhancing our understanding of the cell dynamics of normal and monosomy 7 cells in MDS.     

Quantitative analysis of pulmonary vascular disease in simple cardiac anomalies with the Down syndrome

Intimal changes and medial thickness of small pulmonary arteries were morphometrically examined in 21 cases of simple cardiac anomalies with the Down syndrome, and their correlations with age and with pulmonary arterial peak pressure were then compared with those of 20 cases of simple cardiac anomalies without the Down syndrome and 17 cases of complete transposition of the great arteries (TGA). Results indicate that (1) intimal changes developed at an earlier age in patients with simple cardiac anomalies and the Down syndrome than in those without the Down syndrome, (2) the intimal changes were more severe than those in simple cardiac anomalies without the Down syndrome at the same level of pulmonary arterial pressure and milder than those in TGA, and (3) the media of small pulmonary arteries in simple cardiac anomalies with the Down syndrome was thinner than the media in cases without the syndrome at the same radius and the same level of pulmonary arterial pressure but thicker than the media in TGA. Retarded development of medial hypertrophy in the Down syndrome or TGA in response to pulmonary hypertension appears to make the pulmonary arteries susceptible to even moderate pressure load and appears to be responsible for early development of severe intimal changes.     

骨髓增生异常综合征435例WHO分型和细胞遗传学分析

目的 探讨我国骨髓增生异常综合征(MDS)WHO亚型分布和细胞遗传学异常特点,并与西方国家进行比较.方法 采用前瞻性方法收集了协作组435例MDS患者,进行WHO分型,采用染色体G显带和荧光原位杂交(FISH)技术进行细胞遗传学分析.结果 MDS中位发病年龄为58(18～90)岁.难治性血细胞减少伴多系发育异常(RCMD)病例比例最高,约占69.6%(303/435),其他亚型依次为难治性贫血伴原始细胞增多(RAEB)24.1%(105/435)、难治性贫血(RA)2.3%(10/435)、不能分类MDS(MDS-U)2.3%(10/435)、难治性贫血伴环状铁粒幼细胞增多(RAS)1.2%(5/435)和5q-综合征0.5%(2/435),而西方国家RA、RAS、5q-综合征比例较高,RCMD亚型比例低于中国.11例染色体检查失败,424例染色体检查成功的染色体克隆性异常率为38.7%(164/424),其中RAEB-Ⅰ异常率最高62.5%(25/40),其次RAEB-Ⅱ 48.4%(30/62)、RCMD 34.5%(102/296).常见的染色体异常依次为:+8为12.7%(54/424)、复杂核型为9.O%(38/424)、染色体易位为7.8%(33/424)、-20q为6.6%(28/424)、-7/-7q为5.2%(22/424)、-5/-5q为4.2%(18/424),而国外最常见的是-5/-5q、-7/-7q、+8、11q及12p/12q异常.以国际预后积分系统染色体预后分组,染色体预后良好组68.2%(289/424),预后中等组19.1%(81/424),预后不良组12.7%(54/424).有17例患者因为异常细胞的比例偏低,染色体检查正常,但FISH检测到低水平的异常.结论 我国MDS的WHO亚型分布与染色体异常分布与西方国家不同.FISH和常规染色体检查相结合,可以提高检测的灵敏度.     

In vivo folic acid supplementation partially corrects in vitro methotrexate toxicity in patients with Down syndrome

Patients with Down syndrome have been found to have characteristic in vivo and in vitro methotrexate toxicity. The in vitro methotrexate toxicity characteristic of Down syndrome can be diminished by the in vivo administration of supplemental high doses of folic acid. A possible explanation for the increased sensitivity to methotrexate which has been documented in patients with Down syndrome may be due to imbalances in nucleotide pools which result from a gene dosage effect and to greater methylation demands. Supplemental folic acid may be beneficial by virtue of a down-regulation of excess gene activity and may also provide needed monocarbons.     

Myelodysplastic syndrome in elderly patients: correlation of CBC with cytogenetic and FISH analysis

Unexplained anemia in the elderly could represent myelodysplastic syndrome (MDS). We assessed the utility of using a fluorescence in situ hybridization (FISH) panel for common chromosomal abnormalities seen in MDS. A total of 101 elderly outpatients with anemia of unknown etiology were evaluated. Complete blood count, bone marrow biopsy, conventional cytogenetic analysis (CC), and FISH panel were reviewed. A total of 21 (21%) of the 101 patients had MDS. A combination of CC and FISH identified chromosomal abnormalities in 17 (81%) of the patients with MDS. The remaining 4 (19%) were diagnosed with MDS based solely on morphologic criteria. Except in two cases, FISH did not reveal abnormalities not already detected by CC. Furthermore, MDS patients infrequently had isolated anemia (14%) as opposed to those without MDS (75%). A MDS FISH panel is not more sensitive than CC in elderly outpatients with unexplained anemia. MDS is more likely if in addition to anemia, leukopenia and/or thrombocytopenia are also present.     

Interphase cytogenetic analysis detects minimal residual disease in a case of acute lymphoblastic leukemia and resolves the question of origin of relapse after allogeneic bone marrow transplantation

We used in situ hybridization with a probe for the X chromosome to study interphase cells of bone marrow and peripheral blood specimens from a male patient with acute lymphoblastic leukemia characterized by hyperdiploidy, including trisomy X. In a posttreatment bone marrow specimen, which was interpreted as a regenerating bone marrow morphologically and which demonstrated a normal karyotype cytogenetically, trisomy X was found in 16 of 1,000 interphase cells. This finding indicated the presence of leukemic cells that were undetected by conventional morphologic and cytogenetic techniques (ie, minimal residual disease). Cytogenetic studies of a relapse specimen obtained after a sex-mismatched bone marrow transplant showed only a normal female karyotype in each of 40 metaphase cells, suggesting that the relapse occurred in donor cells. However, interphase analysis demonstrated trisomy X in more than 80% of interphase cells and indicated that the relapse was of the original clone and was not a transformation of donor cells. This case illustrates that interphase analysis can be useful as an adjunct to conventional cytogenetic analysis in the detection of minimal residual disease and in the analysis of interphase cells that are not accessible to routine cytogenetic methods. It also illustrates that previously reported instances of relapse of leukemia in donor cells could have been incorrect if supported by cytogenetic data alone.     

Sweet's syndrome associated with myelodysplasia: possible role of cytokines in the pathogenesis of the disease

Summary. The clinical course of a 56-year-old female patient with Sweet's syndrome (SS) preceded by a myelodysplastic syndrome (MDS) is described. During the acute phase of the disease with high remittent fever, painful skin lesions and maximal leucocytosis IL-6 and G-CSF serum levels were extremely high, while TNF-alpha was only slightly elevated and gamma-interferon and IL1-β were not increased. On clinical improvement IL-6 serum levels rapidly fell, whereas G-CSF values already slightly elevated before the manifestation of the disease slowly declined.
High G-CSF levels triggered by a yet unknown factor could explain the leucocytosis, neutrophilic dermatosis and skin lesions in SS, while IL-6 probably induced the associated clinical symptoms of fever and pain.